BPH is a common disorder in elderly men, occurring in approximately 50% of men aged 60 years and in 90% of those aged 85 years. BPH is a specific histopathological entity characterized by stromal and epithelial cell hyperplasia.
For over a century, the two known etiologic factors for the pathogenesis of BPH have been aging and the presence of functional testes. However, as the science of prostate biology advances, this concept becomes inadequate as it does not cover all aspects of BPH pathogenesis. Additional etiologic factors play a significant role in regulating prostatic growth. In particular, evidence has emerged that prostatic growth is under the immediate control of specific growth factors produced by prostatic cells, acting locally on adjacent cells in a paracrine mechanism or to the same cells in an autocrine mechanism. Therefore much effort is currently being put into identifying therapeutic strategies aimed at inhibiting intraprostatic growth factors.
BPH is a common cause of chronic lower urinary tract symptoms which may affect both the filling (irritative symptoms) and voiding (obstructive symptoms) phases of the micturition cycle. These symptoms affect the social, psychological, domestic, occupational, physical and sexual lives of the patients leading to a profound, negative impact on their quality of life. In addition to this, BPH can cause more acute urological complications, particularly acute urinary retention (AUR), often considered the most serious complication of BPH and less frequently recurrent urinary tract infections, upper urinary tract dilatation, bladder stone formation and recurrent hematuria.
BPH management is associated with extremely high social costs, estimated to be 4 billion dollars in 1993 and projected to be 26 billion dollars in 2003 in the USA alone.
The current medical treatment for BPH consists of orally administered 5 alpha reductase inhibitors (finasteride and dutasteride, recently approved by the FDA) and alpha 1 receptor antagonists (terazosin, doxazosin, tamsulosin as well as silodosin, AIO-8507L, RBx-2258 etc). Each of these therapeutic options is associated with both advantages and disadvantages relating to their different mechanisms of action. Although alpha 1 receptor antagonists are very effective in reducing symptoms related to lower urinary tract symptoms (LUTS), they are ineffective in reducing the prostate volume and therefore in preventing BPH-related surgery. Conversely, 5 alpha reductase inhibitors like finasteride and dutasteride, by decreasing dihydrotestosterone (DHT) formation, reduce prostate size and the need for surgery.
In addition, recent results from the seven-year Prostate Cancer Prevention Trial, involving more than 18.000 healthy aged man, demonstrated that finasteride can prevent or delay the appearance of prostate cancer (see Thompson I M, et al. New England Journal of Medicine (2003) 349 p 215-224). However, as expected (see Kassabian V S, Lancet (2003) 361 p 60-62), finasteride was not free from anti-androgenic adverse effects on sexual function, such as decreased sexual potency, sexual desire and gynecomastia, that substantially lessen its attractiveness as a cancer-preventing agent. In addition, finasteride treatment was associated with an increased detection of high-grade prostate cancer, probably because the finasteride-induced low androgen state selected the most aggressive, androgen-insensitive malignant growing cells (see Scardino P T, New England Journal of Medicine (2003) 349 p 297-299).
Thus there is an unmet need for a new class of drugs for medical therapy of BPH, which should be able to prevent acute urinary retention, together with its related need for surgery, by decreasing androgen-induced prostate growth but without directly interfering with androgen receptors (AR), and therefore without anti-androgenic prostatic and extra-prostatic adverse effects, for example, sexual side effects. Such medicaments, by disrupting intra-prostatic growth factor signalling, might be useful not only for treating BPH but also for preventing prostate cancer, possibly without selecting AR-insensitive, malignant clones.